Device and method for physiochemical measurements

ABSTRACT

The invention relates to a microfabricated device for use in measuring the physical properties of compounds, where the properties measured using such devices are those which involve partitioning of the compound between two phases, measuring partition coefficients, distribution coefficients, acid-base dissociation constants, solubility and vapour pressure. The device comprises a microfabricated conduit, in which two fluids flow creating at least two phases between which the compound may partition, and a detector for measuring the amount of compound in each or both fluids.

The invention relates to a microfabricated device for use in measuringthe physical properties of compound samples, where the propertiesmeasured using such devices are those which involve partitioning of thecompound between two phases, measuring partition coefficients,distribution coefficients, acid-base dissociation constants, solubilityand vapour pressure.

BACKGROUND OF THE INVENTION

The biologically active compound, for example a pharmaceutical oragrochemical compound, depends on a range of physicochemical andbiopharinaceutical attributes of that compound which governs thebioavailability of the compound in the target and non-target species ortissue or organism or at a target or non-target enzyme or molecule. Inorder to accelerate the rate of discovery of such molecules, there iscurrently considerable interest in the measurement of such propertiesfor large numbers of compounds very early in the discovery process sothat these factors may be used to influence future decisions on whichmolecules to synthesis as potential candidates for drug or agrochemicalresearch programs.

Synthetic techniques such as multiple parallel synthesis (MPS) andcombinatorial chemistry provide relatively small sample sizes, forexample in the microgram range. The limited sample sizes currentlyproduced are not large enough to supply more than a few tests within thedrug discovery process before the supply is exhausted. Therefore,resynthesis may be required in order to restock the chemical library.

Candidate compounds of potential interest may therefore only beavailable in relatively small amounts i.e. <1 mg. There is therefore astrong need for methods that can be applied to large numbers ofcompounds without requiring proportionately more resources and which arecapable of dealing with small sample weights. Conventional methods oftenemploy complex separation steps which are time-consuming. Although thesecan be automated, the serial nature of the analysis i.e. one sample at atime, still effectively limits the throughput.

Microfabrication techniques are generally known in the art using toolsdeveloped by the semiconductor industry to miniaturise electronics, itis possible to fabricate intricate fluid systems with channel sizes assmall as a micron. These devices can be mass-produced inexpensively andare expected to soon be in widespread use for certain simple analyticaltests. See, e.g., Ramsey, J. M. et al. (1995), “Microfabricated chemicalmeasurement Systems,” Nature Medicine 1:1093-1096; and Harrison, D. J.et al (1993), “Micromachining a miniaturized capillaryelectrophoresis-based chemical analysis system on a chip,” Science261:895-897. In addition devices have been proposed for preparative,analytical and diagnostic methods which bring two streams of fluid inlaminar flow together which allows molecules to diffuse from one streamto the next, examples are proposed in W09612541, WO9700442 and U.S. Pat.No. 5716852.

Miniaturisation of laboratory techniques is not a simple matter ofreducing their size. At small scales different effects become important,rendering some processes inefficient and others useless. It is difficultto replicate smaller versions of some devices because of material orprocess limitations. For these reasons it is necessary to develop newmethods for performing common laboratory task on the microscale.

DESCRIPTION OF THE INVENTION

We have found that it is possible to measure in a microfabricated devicephysical properties such as the physicochemical, biopharmaceutical orenvironmental properties of a compound, or material containing acompound, if it is allowed sufficient time to partition between twophases where at least one phase is then analysed to provide theinformation for determining the physical property.

Biopharmaceutical properties include, for example, protein binding, invitro metabolism, passive and active membrane transport. Environmentalproperties include, for example, soil binding, soil metabolism,water:air distribution and leaching. Physicochemical properties include,for example, partition coefficients, distribution coefficients,acid-base dissociation constants, solubility and vapour pressure.

Accordingly, we present as a first feature of the invention a method forthe measurement of one or more physical property of a compound in amicrofabricated device which method comprises;

(i) providing through an internal surface defining a conduit of themicrofabricated device a flow of a fluid and present within the fluid isa compound;

(ii) moving the fluid through the conduit to bring it into contact withan agent to allow any partitioning of the compound through a partitioninterface formed between the fluid and the agent;

(iii) measuring the amount of compound or a derivative of the compoundpresent during and/or after partitioning between the fluid and the agentin either the fluid or the agent, or both.

We present as a further feature of the invention a system for thedetermination of at least one physical property of a compound whichcomprises:

(i) a microfabricated device having an internal surface defining aconduit through which fluid may flow, compound being present in thefluid.

(ii) the conduit containing an agent to which the fluid is brought intocontact:

(i) a detector for measuring the amount of compound or compoundderivative present within the fluid or the agent or both; whereinpartitioning of the compound through a partition interface formedbetween the fluid and the agent and presence of compound in either thefluid or the agent or both is measured to determine the physicalproperty.

In this disclosure, the term “agent” may be any substance into which thecompound may partition. The exact agent used will depend upon thephysical property being measured. The agent may, for example, be a fluidor solid or semi-solid material. The agent may consist of or containmaterials including chemical or biological reagents, membrane(s),cell(s), cell fragment(s), and mixtures of such materials. Preferablythe agent is a fluid. Fluid agent may contain dissolved or suspendedmaterials including chemical or biological reagents, membrane(s),cell(s), cell fragment(s), and mixtures of such materials. Preferablythe agent is a fluid.

In this disclosure, the term “fluid” is significant as it is the fluidsthat define the nature of the phases between which the compound will, ifable, partition. The fluid may itself be the compound, with or withoutother fluids, or may be a solvent for the compound. The fluid may be agas, vapour, liquid or supercritical fluid (gas or liquid). The fluidmay also be a mixture of different fluids. The fluid will be chosenaccording to the physical property being measured. Preferably the fluidis a liquid.

In this disclosure the term “partition interface” means a point orpoints at which the fluid and the agent contact each other and a surfaceforming boundary is made through which the compound must pass forpartition to occur. Alterbatively, “partition interface” means a pointor points at which a further third fluid is present which itself forms aboundary between the fluid and the agent.

In this disclosure, the term “microfabricated” includes devices capableof being fabricated on polymeric, ceramic, glass, silicon wafers(preferably monocrystalline silicon), or other suitable materialsavailable to those practising the art of microfabrication and having thefeature of sizes and geometries producible by microfabricationtechniques. Microfabrication techniques include such methods as,photoligraphy, LIGA, thermoplastic micropattern La transfer, resin basedmicrocasting, micromolding in capillaries (MIMIC), wet isotropic andanisotropic etching, laser assisted chemical etching (LACE), andreactive ion etching (RIE), or other techniques known within the art ofmicrofabrication. In the case of silicon microfabrication, larger waferswill accommodate a plurality of the devices of this invention in aplurality of configurations. A few standard wafer sizes are 3″ (7.5 cm),4″ (10 cm), 6″ (15 cm), and 8″ (20 cm). Application of the principlespresented herein using new and emerging microfabrication methods iswithin the scope and intent of the invention. Microfabricated devicesare created through innovative combinations of three essentialmanufacturing processes: (1) photolithography, the optical process ofcreating microscopic patterns (2) etching, the process that removessubstrate material and (3) deposition, the process whereby materialswith a specific function can be coated onto to surface of the substrate.

By “partitioning” we mean that the compound is allowed to move, if able,from the fluid to the agent. This partitioning may be allowed to reachequilibrium before measurements are taken, or measurements may be takenprior to equilibrium being reached. However, it will be appreciated thatit may be advantageous in terms of time, as described below withreference to diffusion path lengths, to take one or more measurementsbefore partition equilibrium and deduce the physical property on thebasis of extrapolation, or on the basis of a calibration curve.

Preferably, where the agent is a fluid, the “second fluid”, then thismay be any fluid as defined above into which the compound may partitionand is a fluid which will form a phase interface when in contact withthe first fluid. The exact fluid used will depend upon the physicalproperty being measured and may be, for example, a fluid which ispartially miscible or non-miscible with the first liquid, a solvent, agas, or any other fluid as defined above in the definition of “fluids”.

The fluid agent and the fluid within which is carried the compound arepreferably non miscible. For immiscble fluids the partitioning interfaceis defined by the physical interface maintained between the two fluids.

Subject to some restrictions the fluid agent and the fluid within whichis carried the compound may be miscible. The two fluids may be misciblewhere a boundary region between the two fluids can be defined andmaintained as by parallel laminar flow and where the diffusive transferof compound through and between the fluids is significantly faster thanthe mixing of the fluids or transfer of dissolved or suspended materialfrom the fluid agent to the fluid containing compound. This may beachieved where material suspended or dissolved in the fluid agentconsists of macromolecules, colloid particles, cells, or cell fragmentswhich have very low diffusion rates compared with the compound.

In this disclosure, the term “compound” refers to any substance ofbiological or chemical origin. Derivatives of the compound are thosewhere the compound has been altered in some way by exposure to theagent, for example, solvated, metabolised, ionised, reduced, oxidised,hydrolysed or dissolved.

In this disclosure the term “non-miscible” means that the two fluids(where at least one fluid is a liquid or a supercritical fluid) do notmix but could partially dissolve in the other, for example,water/octanol.

We present as a feature of the invention a method for the measurement ofone or more physical property of a compound in a microfabricated devicewhich comprises;

(i) providing through an internal surface defining a conduit of themicrofabricated device a flow of fluid in which is present the compound;

(ii) bringing the flow of fluid into contact with a second fluid withinthe conduit for a sufficient period for any possible partitioning of thecompound through a partition interface formed between the two fluids tooccur;

(iii) measuring the amount of compound or derivative of the compoundpresent after partitioning in either the fluid or the second fluid, orboth.

We present as a further feature of the invention a method for themeasurement of one or more physical property of a compound in amicrofabricated device which method comprises;

(i) providing through an internal surface defining a conduit of themicrofabricated device two liquids;

(ii) the first liquid contains a compound, the second liquid isnon-miscible with the first liquid;

(iii) bringing the two liquids together, preferably in parallel laminarflow, for a sufficient period for any possible partitioning of thecompound through a partition interface formed between the two fluids tooccur;

iv) measuring the amount of compound or derivative of the compound inthe first liquid, the second fluid, or both.

In an alternative feature of the invention the first and second fluidsare flowed along first and second conduits which converge, contact andthen run parallel to one another with one or more restricted openingsbetween the conduits thus forming a contacting conduit within which atthe opening(s) contact is established between the two fluids. Parallellaminar flow is maintained for each fluid in their respective portionsof the contacting conduit and such transfer of compound through theopening(s) between the portions of contacting conduit occurs as isconsistent with possible partitioning of the compound between thefluids. Conduits may diverge from the contacting region separating thetwo fluids. This structure indicated diagramatically in FIG. 4 hasadvantages for maintaining stable contact between to flows of immisciblefluids.

The term parallel laminar flow means stable flow of the liquid throughthe conduit, there being no areas of turbulence. Therefore the presenceof compound or compound derivative in the second liquid is entirely dueto the ability of the compound to partition between the first liquid andthe second liquid, i.e. its physical properties. See FIG. 4.

The term parallel laminar flow means that stable flow of fluid existsthrough a conduit with no regions of turbulence. Laminar flow isconsistent with the low Reynolds number flow conditions which generallyapply for low to moderate rate flows of liquids through channels ofmicroengineered dimensions. Where contact between the fluids isestablished under parallel lamianr flow conditions, the presence ofcompound or deivative is entirely due to the ability of the compound todiffuse to and from the interface between the two fluids and topartition across the interface. By ensuring that diffusion distancesacross the conduits are sufficiently short to allow rapid diffusivetransfer to and from the interface, conditions are established to allowthe partition to proceed speedily to equilibrium. Measurements fluidflow ratios and of compound concentration in one or both fluids thenallows calculation of the desired physical property. Measurements ofconcentration at multiple points along the conduits allows progresstowards equilibrium to be monitored and flow rates to be selected so asto ensure that fluid contact time is sufficient for equilibrium to besubstantially achieved. See FIG. 4.

Typically, for liquids the conditions for parallel laminar flow andrapid diffusive transfer of compound are met where the width of eachportion of the contacting conduit is of the order of 100 μm or less.Preferably the microfabricated conduits which contain the contactingflows have a constant width and smooth internal surfaces.

The fluids may be propelled by means of a mechanical pump, by syringedrive, by applying a vacuum or pressure to one end of the channel, bygravity flow or by electro-osmosis. A preferred method iselectro-osmosis, which may conveniently be achieved by themicrofabrication of electrodes at the ends of the conduit, the voltagesbetween electrodes being controlled conveniently externally to achievethe desired fluid movements. The fluids may be moved at variable ratesin accordance with the method chosen. Each compound may be moved in thefluids creating the two phases to allow partition to occur during afixed time period for each compound to provide information on theranking of the compounds in a qualitative analysis rather than aquantitative measurement of the physical property.

We present as a further feature of the invention a method for themeasurement of one or more physical property of a compound in amicrofabricated device which method comprises;

(i) providing through an internal surface defining a conduit of themicrofabricated device two moving fluids;

(ii) the first fluid contains compound;

(ii) the second fluid is non-miscible with the first fluid;

(iii) the two fluids moving together in the microfabricated conduit incontact with each other to allow a phase interface between the twofluids to form and allowing any possible partitioning of the compoundfrom the first fluid to the second fluid to occur;

iv) measuring the amount of compound or derivative of the compound inthe first fluid and/or the second fluid.

Due to the smaller quantities of fluid and sample which are used,diffusional distances within the fluid can be dramatically loweredallowing for equilibrium to be reached efficiently without the need forconvective or advective mixing. However movement of the fluids throughthe conduit may be usefully employed to enhance or control mixing ratesby taking into account possible advective mixing which may be caused bydrag with the surface of the conduit.

Different compounds will reach the point of partition equilibrium atdifferent rates, this is known as the rate of partition. The rate ofpartition of a sample may be affected by many different factors such aschemical kinetic factors and transport of dissolved material in thesolvent by convective, advective, or diffusive processes. Withinmicrofabricated conduits it is possible to limit convective or advectiveand in particular turbulent fluid transport so that diffusion may be thedominant mode of transport of the compound through the fluid. Wherediffusive transfer is the limiting factor, the partition rate is relatedto the length of the path through which the compound molecules diffuseand the geometry of the fluid body in the conduit. Diffusive transferrates will generally be inversely related to the square of the pathlength.

Typically diffusion coefficients (D) of samples of the size range ofinterest (MW of a few hundred) will be around 5×10⁻⁶ cm²s⁻², in aliquid, and have diffusive transfer times (t) across a path length (L)which may be derived from expressions of the type Dt/L²=0.01 to 1second, where Dt/L²=0.01 approximates to a diffusion front reaching adistance across L from source plane, and Dt/L²=1 corresponds to nearcompletion of the diffusive process (concentration gradient across Lbeing nearly eliminated). Approximate times for reaching diffusiveequilibration (Dt/L²=1) at different path lengths (L), in which thedissolved compound must travel, based on D=5×10⁻⁶ cm²s⁻¹ are:

L = 10 μm t = 0.2 sec L = 100 μm t = 20 sec L = 1 mm t = 0.5 hours L = 1cm t = 55 hours

About 50% of the diffusive transfer will occur in about a tenth of theabove times. Based on the above, the condition for relatively rapidequilibration (˜<100 seconds) by diffusion alone can be met where thedistance L across the liquid from a partition interface, generally aconduit width, is not greater than 100 μm and flow rates set to allowcontact times between portions of first and second fluids of ˜100seconds or greater. This has impact on liquid volume, depending ongeometry of the device, and especially the contact conduit length andwidths, i.e. preferably fluid volumes in the contact conduit region atany time will be in the range 1 nl to 1 μl, and preferably in the range10 nl to 100 nl. Larger volumes of the two fluids may be used bycontinuing the flow of first and second fluids through the contactregion for any desired time.

For relatively rapid equilibration to occur, the diffusion path lengthstypically encountered impose limitations on the dimensions of the fluidbodies and the enclosing microfabricated conduits in the contact region.For example we have found that where the fluids are liquids, the longestfluid dimension perpendicular to the contact interface should be in arange from 1 mm to 1 μm and preferably in a range from 100 μm to 1 μm.It will be appreciated that the corresponding length for the fluid, whenit is a gas, could be significantly larger due to the faster rate ofdiffusion. Typically gaseous diffusion coefficients are of the order of0.1 cm²s⁻¹ and therefore diffusion lengths, and corresponding conduitwidths, could be in the range 3 cm to 100 μm, preferably in the range 5mm to 500 μm.

The conduit may be any shape in cross section, preferably it is round orelliptical with a smooth internal surface.

The consequent limitation on fluid path length can however be readilyremoved if the liquid is mixed by convective/advective processes withinthe device and this is a further feature of the invention. Movement of aportion of fluid along a conduit causes recirculation within thatprotion of fluid and thus transferring any compound present in the fluidfrom the ends of the fluid portion into the interior of the fluidportion. In addition changing the geometry of the liquid may greatlyimprove diffusion rates by shortening the diffusion path length, compareFIGS. 1 and 2 where a larger volume of liquid could be used in FIG. 2than FIG. 1 and still only a reasonable diffusion time in both is neededto reach partition equilibrium.

Typical amounts of compound which may be used in this device range from1 ng to 1 mg. Typical volumes of fluid used in this device range from 1nl to 0.1 ml, the minimum liquid volume corresponds to a 100 μm sidecube, depending upon whether the fluid is a liquid or a gas.

The conduit may be any shape in cross section, preferably it is round orrectangular with a smooth internal finish.

Limitations on fluid path length imposed by diffusive transfer can bereadily removed if the liquid is mixed by convective/advective processeswithin the device and this is a further feature of the invention. Inaddition changing the geometry of the liquid may greatly improvediffusion rates by shortening path length. Where first and second fluidsare brought into contact as sequential lengths of fluid or flows flowingalong a conduit, recirculatory advective movement of fluid within flowsinduced by slug movement conveys material to and from the slug endinterfaces at rates which can be very significantly higher than thosefor diffusion. In particular the recirculatory fluid transport ofmaterial within the fluid of a slug will proceed at rates linearlyrelated to the rate of movement of the slug along a conduit andtransport times from the slug end surface to the interior will increaselinearly with distance from the interface rather than with the square ofdistance as for diffusion.

Advective mixing within flows of fluid may be achieved both by flow in asingle direction and also by reciprocating flow where the direction ofmovement of the flows along a conduit is periodically reversed. Use ofreciprocating flow allows a more compact device construction as thelength of conduit required to carry out the partitioning transfer isreduced.

Section of slug flow with first and second fluids may be separated byslugs of a third fluid chosen to be immiscible with either andpreferably both first and second fluids and also chosen not to providesignificant partion capacity for the compound or other materialsdissolved or suspended in the first and second fluids. Where the firstand second fluids are liquids or supercitical fluids, the third fluidmay conveniently be a gas.

Within a slug diffusion rates perpendicular to the axis of flow will berelated to the distance from axis to the confining walls of the conduitand thus to half the conduit width. This allows either faster diffusivetransport for the same conduit width compared to that for diffusionbetween parallel contacting conduits, or allows the use of widerconduits without gross increase in diffusion times.

FIG. 1 represents the movement of immiscible fluid flows along a conduitwith material transfer between adjacent flows. Such transfer based onsequential flows of first and second fluids can only be applied wherethose fluids are immiscible as it relies on surface tension effects tomaintain the interfaces and prevent transfer of material between thefluids by advective flow.

In addition to the use of adjacent flows of first and second fluids in asimple conduit, the method can be extended so that partion can becarried out using adjacent flows in parallel conduits with restrictedopening between the conduits. The first and second fluids flow in firstand second contacting conduits with a third fluid separating flows offirst or second fluid or both. This arrangement shown in FIG. 2 has theadvantage of providing increased contact area between the first andsecond fluids whilst providing the advective mixing associated withmovement and relatively short diffusion lengths.

Preferably the two fluids are brought together so that the phaseinterface is created at the point at which the two fluids contact eachother and is formed in the conduit so the phase interface isapproximately at 90° to the direction of flow of fluid—see FIG. 1, forexample. Alternatively the phase barrier is approximately in the sameplane to the direction of flow of fluid—see FIG. 2, for example.

Since both fluids are moving this allows serial analysis of samples inthe same conduit in a continuous manner. By multiplying the number ofconduits serial experiments may be performed in parallel tosignificantly further improve productivity.

When performing serial analysis in the same conduit it is important toallow a gap between the introduction of the first set of two fluids toprevent contamination by the second set of two fluids. A barrier plugmay be inserted between each batch of two fluids. This barrier plug maysimply be a gap in the introduction of the fluids, or an adiitionalfluid or solid, into which compound cannot partition. It will beappreciated that by reference to two fluids we mean that two differentfluids are inserted but that each fluid may be inserted more than once.For example fluid 1 may be inserted first, then fluid two and then fluid1 so that two phase interfaces are created between the first and secondfluids one either side of the second fluid—see FIG. 1.

In the invention the detection and measurement of the compound orderivative of the compound may be achieved either “on” the device or“off” the device or a combination of both. Suitable methods fordetermination using an on or off-device include potentiometry,conductiometry, mass spectrometry or methods of chromatography such as:capillary electrophoresis, high performance liquid chromatography (HPLC)or capillary electro chromatography with a variety of detection methodssuch as ultra violet (UV) or mass spectrometry (MS) Alternatively thechromatographic separation could be carried out on-device with detectionsuch as UV or MS being carried out off the device. The attachment of anoff-device detector to a microfluidic systems has been demonstrated inBings N. et al. Proceedings of the μTAS'98 Workshop, Kluwer AcademicPublishers, 141.

In the case of off-device detectors, a suitable interface to themeasuring equipment will be required. In the case of mass spectrometry,suitable interfaces have already been described in Xue-Qifeng,Dunayevskiy-Yuri-M, Foret-Frantisek, Karger-Barry-L. Rapid Commun MassSpectrom, VOL: 11 (12), P: 1253-1256, 1997. Further developments indevice interfacing may be expected and are hereby incorporated into thedevice and methods of the invention.

It also may be desirable to measure using on or off-device methods theamount or concentration of compound present in the inlet stream prior topartitioning.

Connections with fluid reservoirs external to the device may be made inaccordance with Mourlas N. J. et al. Proceedings of the μTAS'98Workshop, Kluwer Academic Publishers 27, and references cited therein.

Devices may be conceived where the measurement of more than one propertyis made simultaneously (e.g. partition coefficient measurements usingseveral different solvents or with the same solvent at several pHs tomeasure pKa) and conversely where the same measurement is made onseveral different compounds.

Methods for the manufacture of the devices of the invention may beadapted from those described in W09612541, W09700442 and U.S. Pat. No.5,716,852.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated by the following non-limiting diagrams.

FIG. 1—shows a schematic diagram of a microfabricated device of theinvention where compound in fluid phase 2 is allowed to partition intothe second fluid 1 . At 3 is a barrier plug which is a fluid or gas soas to prevent contamination. Fluids 1 and 2 and barrier 3 flow down theconduit.

FIG. 2—shows a schematic diagram of a microfabricated device of theinvention where compound in fluid 2 is allowed to partition into thesecond agent 1. At 3 is a barrier plug which is a fluid or a gas so asto prevent contamination. Fluids 1 and 2 and barrier 3 flow down theconduit.

FIG. 3—shows a schematic diagram of a microfabricated device of theinvention where compound in a liquid from a compound sample container 1is brought into contact with the agent 2 and the amount of compound ineach partition is measured at suitable detection points

FIG. 4—shows a schematic diagram of a microfabricated device formeasuring the logP of compound where compound in an aqueous liquid froma compound sample container 1 is brought into contact with the agent 2flowing from an agent container 4 parallel laminar flow which in thiscase is an organic solvent. UV light is shone through themicrofabricated device and the amount of compound in each partition ismeasured by MS at suitable detection points 3. As can be seen the ????flow of the two liquids may be separated at the detection point to moreeasily measure the amount of compound present in the organic solvent.

What is claimed is:
 1. A system for the determination of at least onephysicochemical property of a compound which comprises: (i) amicrofabricated device having an internal surface defining a firstconduit; p1 (ii) a first fluid through said first conduit, said compoundbeing present in the first fluid; (iii) a second conduit in saidmicrofabricated device; (iv) a second fluid flowing through said secondconduit, said second fluid being non-miscible with said first fluid; (v)one or more restricted openings being present between the first andsecond conduits to allow contact between the first and second fluids atthe one or more restricted openings via a partition interface formedbetween the first fluid and the second fluid, the partition interfacebeing formed by contact between the first fluid and the second fluid;(vi) a detector for measuring the amount of the compound present withinthe first fluid or the second fluid or both; wherein presence ofcompound in either the first fluid or the second fluid or both ismeasured to determine the physicochemical property due to thepartitioning of the compound through the partition interface.
 2. Asystem as claimed in claim 1 which additionally comprises means formoving the first and/or the second fluid through the first and/or secondconduits.
 3. A system as claimed in claim 1 wherein the detector is anintegral part of the microfabricated device.
 4. A system according toclaim 1 in which the partition interface formed between the first fluidand the second fluid is formed by a third fluid.
 5. A method for themeasurement of at least one physicochemical property of a compound in amicrofabricated device which method comprises: (i) providing through aninternal surface defining a conduit of the microfabricated device a flowof a first fluid and present within the first fluid is a compound; (ii)moving the first fluid through the conduit to bring it into contact witha second fluid via a partition interface formed between the first fluidand the second fluid to allow any partitioning of the compound throughthe partition interface, said second fluid being non-miscible with saidfirst fluid, the partition interface being formed by contact betweennon-miscible phases; (iii) measuring the amount of the compound presentduring and/or after partitioning between the first fluid and the secondfluid in either the first fluid or the second fluid, or both.
 6. Amethod as claimed in claim 5 wherein the first and second fluids areliquids.
 7. A method as claimed in claim 5 wherein a second set of firstand second fluids is introduced into the conduit after introduction of abarrier plug.
 8. A method according to claim 5 in which the partitioninterface between the first fluid and the second fluid is formed by athird fluid.
 9. A method according to claim 5 in which thephysicochemical property is partition coefficient.
 10. A methodaccording to claim 5 in which the first fluid flows through a firstconduit and the second fluid flows through a second conduit, the firstand second fluids contacting via a partion interface at one or morerestricted openings between the first and second conduits.
 11. A methodaccording to claim 5 in which the first and second fluids are broughtinto contact as sequential lengths of fluid flowing along the conduit.12. A method according to claim 11 in which the direction of movement ofthe flows is periodically reversed.
 13. A method according to calm 11 inwhich the second fluid is firstly inserted, secondly the first fluid isinserted and then thirdly the second fluid is inserted a second time inthe conduit.
 14. A method according to claim 13 in which the directionof movement of the flows is periodically reversed.
 15. A methodaccording to claim 11 in which the first fluid is firstly inserted,secondly the second fluid is inserted and then thirdly the first fluidis inserted a second time in the conduit.
 16. A method according toclaim 15 in which the direction of movement of the flows is periodicallyreversed.